Right ventricular (RV) failure is by far the most common cause of death in patients with pulmonary arterial hypertension (PAH). At present, little is known of the mechanisms contributing to RV failure in the setting of PAH. It is increasingly appreciated that it is not due simply to distal pulmonary microvascular disease and high pulmonary vascular resistance but rather to complex interactions between the pulmonary circulation and the RV. Inflammation is known to contribute significantly to changes in vascular remodeling in both large and small vessels as well as to RV dysfunction, especially in scleroderma associated PAH (SSc-PAH). Circulating mononuclear-fibrogenic cells have been implicated in inflammation, vascular remodeling, and RV dysfunction by our group and others. We have shown that fibroblasts in PAH patients and in animal models acquire an activated and epigenetically altered phenotype that is capable of generating a microenvironment, which promotes recruitment and activation of circulating mononuclear fibrogenic cells and that these cells contribute directly to tissue fibrosis and cardiac dysfunction. Our proposal will directly examine the mechanisms involved in fibroblast directed recruitment and activation of mononuclear fibrogenic cells and ultimately the role of these cells in driving abnormalities of large and small vessels, RV function and ultimately RV failure. Studies will be conducted in patients and also in unique large animal models of disease that have great fidelity to the human condition. Further, because we have shown that histone modifications are involved in the epigenetic change in fibroblast phenotype and that histone deacetylase inhibitors (HDACi) can turn off inflammatory signaling by activated fibroblasts, we will pursue studies to determine whether isoform selective HDAC inhibition can reverse pre-existing pulmonary hypertension and cardiac dysfunction by reprogramming epigenetically imprinted pro-inflammatory fibroblasts in the vasculature and right ventricle. Our proposal involves a multi- disciplinary approach with Principal Investigators with expertise in clinical pulmonary hypertension, in molecular cardiology, and in cell and molecular biology of fibroblasts and circulating mononuclear cells. Collectively, work by this interdisciplinary group will provide insight into abnormalities of RV-pulmonary arterial interactions in the setting of severe pulmonary hypertension and will lay the groundwork for potential new therapies.